PHILADELPHIA -- The fat in obese patients is not as healthy as that in leaner individuals, researchers found.

Action Points

Explain to interested patients that this study found that fat in obese patients demonstrates endoplasmic reticulum stress, whereas that in leaner patients does not.

Point out that the researchers said that endoplasmic reticulum stress may be one explanation for insulin resistance in obese patients.

PHILADELPHIA, Aug. 27 -- The fat in obese patients is not as healthy as that in leaner individuals, researchers found.

Adipose tissue samples taken from nondiabetic obese patients showed increased expression of proteins linked to endoplasmic reticulum stress, which may play a role in insulin resistance, Guenther Boden, M.D., of Temple University here, and colleagues reported in the September issue of Diabetes.

The bottom line of their finding is that there is something fundamentally different in the fat of obese persons and the fat of lean persons that may explain some of the pathology of obesity.

"The fat cells we found in our obese patients were deficient in several areas," Dr. Boden said. "They showed significant stress on the endoplasmic reticulum, and the tissue itself was more inflamed than in our lean patients."

"The implication is that having too much fat is not just a cosmetic problem," he continued. "That fat is unhealthy and dysfunctional, and you ought to do something about it because you'll have consequences that affect other organs in your body."

Although the association between obesity, insulin resistance, and inflammation is well known, the causes are not completely understood, the researchers said.

Free fatty acids likely play a role, but not all obese, insulin-resistant patients have elevated levels, they said.

Another candidate is endoplasmic reticulum stress, which has been linked to chronic excessive nutrient intake in mouse models of obesity, although exact mechanisms causing the stress remain unclear.

To find out whether endoplasmic reticulum stress exists in the fat of obese individuals, the researchers obtained fat samples from the upper thighs of six lean (mean age 36) and six obese (mean age 44) patients.

The obese patients were significantly more insulin resistant (P<0.05).

Proteomic analysis showed that there were 19 proteins differentially upregulated in the adipose cells of obese patients. Six were related to endoplasmic reticulum stress and the unfolded protein response, which is initiated when the endoplasmic reticulum is overloaded by unfolded or misfolded proteins, four were related to energy and free fatty acid metabolism, four were structural proteins, and four were involved in protein transport and signaling.

As the latter protein "can inhibit insulin action and activate proinflammatory pathways, endoplasmic reticulum stress activation of [the protein] may be a link between obesity, insulin resistance, and inflammation," the researchers said.

Reverse transcriptase PCR showed that X-box binding protein-1s, another protein related to stress, and the proinflammatory cytokine tumor necrosis factor-alpha were also upregulated in obese patients.

Upregulation of other proteins indicated cytosolic and mitochondrial, in addition to endoplasmic reticulum, stress.

Dr. Boden said that the simplest explanation for the endoplasmic reticulum stress in the fat of obese patients is that the cells are overwhelmed.

"It has been speculated that the reason for endoplasmic reticulum stress in response to nutrient excess may be increased demand for lipid and protein synthesis and for structural changes in the organs primarily involved in metabolizing and storing excess nutrients," the researchers said.

That explanation is consistent with the upregulation of structural and transport proteins and those related to energy and fat metabolism found in the study, they said.

The researchers noted that "the results may not be representative of fat in other locations."

The study was supported by grants from the NIH and the Groff Foundation, as well as a Mentor-Based Training Grant from the American Diabetes Association.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco